tbuckley/cabot-search huggingface dataset:
PB2003: REAL-WORLD DURATION OF USE AND DOSING FREQUENCY OF DARATUMUMAB IN PATIENTS WITH MULTIPLE MYELOMA IN THE U.S.
Authors: R. Fonseca, E. Chinaeke, N. Gupta, A. Fu, T. Ran, S. Kaila
Journal: HemaSphere (2022)

Background: Daratumumab (DARA) is an anti-CD38 monoclonal antibody approved for treatment of patients with newly diagnosed and previously treated multiple myeloma (MM). Hence, it is possible that patients initiating DARA may continue to use it as backbone of their treatment even if their line of therapy (LOT) or treatment regimen changes, sometimes with interruptions. Aims: This study examines the continuous duration of DARA treatment and dosing frequency across all LOTs using real-world data from MM patients in the U.S. Methods: This is a retrospective observational study conducted using Optum Clinformatics Data Mart database consisting of some Medicare and commercially insured MM patients utilizing DARA, between 11/1/2015-3/31/2021. Duration of DARA use was defined as the time interval between first initiation and discontinuation of DARA spanning multiple LOTs as a time-to-event outcome using Kaplan-Meier method. A gap of >60 days between two consequent DARA claim dates was defined as DARA discontinuation. Dosing frequency was calculated as the average number of DARA doses during defined time periods. Compliance ratios were calculated as observed dosing frequency divided by the dosing frequency for FDA approved regimens (DARA-Lenalidomide-Dexamethasone [DRd] and DARA-Pomalidomide-Dexamethasone [DPd]). All results were calculated for patients using DARA across multiple LOTs regardless of treatment regimen. Results: A total of 2125 patients initiating DARA therapy were included in this analysis with mean age (SD) of 70.9 (9.8) years, 51.3% males, and 64.8% white. The median length of DARA use spanning multiple LOTs, was 16.6 months. During the first year of DARA use, 90.5%, 83.2%, 72.6% and 63.5% of the patients continued DARA at 3, 6, 9, and 12 months, respectively. At years 2 and 3 of DARA use, 33.1% and 14.5% of the patients, respectively, continued DARA treatment (Figure 1). The mean dosing frequency in real world was similar to the dosing frequency on the approved label (Table 1). The compliance ratio was 0.98 over the period of 36 months. Table 1. - Real-world dosing frequency of daratumumab over 36 months of follow-up (N=2125) Follow-up Period (in months) % of original sample remaining Number of Daratumumab doses from RWDMean (SD) Number of Daratumumab doses based on PI Compliance ratio 0-3 90.5% 9.6 (2.4) 11 0.87 0-6 83.2% 15.0 (3.1) 17 0.88 0-9 72.6% 18.5 (3.4) 20 0.92 0-12 63.5% 22.0 (3.8) 23 0.96 0-18 46.5% 28.8 (4.6) 30 0.96 0-24 33.1% 35.4 (6.0) 36 0.98 0-36 14.5% 48.1 (8.6) 49 0.98 Abbreviations: RWD, real world data; SD, standard deviation; PI, prescribing information for DRd and DPd as approved label Image:Summary/Conclusion: Patients initiating DARA remain on the therapy for a median of 16.6 months with one-sixth continuing DARA beyond 3 years. The dosing frequency observed in the real-world was consistent with the approved label.
Classification of <i>BRCA2</i> Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay
Authors: Chunling Hu, Lisa R. Susswein, Maegan E. Roberts, Hana Yang, Megan L. Marshall, Susan Hiraki, Windy Berkofsky-Fessler, Sounak Gupta, Wei Shen, Carolyn A. Dunn, Huaizhi Huang, Jie Na, Susan M. Domchek, Siddhartha Yadav, Alvaro N.A. Monteiro, Eric C. Polley, Steven N. Hart, Kathleen S. Hruska, Fergus J. Couch
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.
Blood Eosinophils and Chronic Obstructive Pulmonary Disease: A Global Initiative for Chronic Obstructive Lung Disease Science Committee 2022 Review
Authors: Dave Singh, Alvar Agusti, Fernando J. Martinez, Alberto Papi, Ian D. Pavord, Jadwiga A. Wedzicha, Claus F. Vogelmeier, David M. G. Halpin
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
PB1798: EVALUATION OF EXPRESSION OF PLODS FAMILY GENES (PLOD1, PLOD2, PLOD3) IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: F. Zaker, A. qorbanpour
Journal: HemaSphere (2022)

Background: AML is a multifactorial disease and different factors play a role in its occurrenc, timely diagnosis and appropriate treatment. On the other hand, due to the importance of PLOD family genes (PLOD1, PLOD2, PLOD3) that lysine hydroxylase enzyme is directly involved in collagen synthesis and extracellular matrix regeneration and their vital role in migration, invasion and angiogenesis in many cancers. Aims: Since the expression of PLOD family genes in AML patients have not been studied so far, also due to the importance of these two risk factors, namely invasion and angiogenesis and the relationship between the expression of these genes and the prognosis of patients, the expression status of PLOD family genes were studied in patients with acute myeloid leukemia. Methods: In this study, the expression of PLOD family genes (PLOD1, PLOD2, PLOD3) in 54 newly identified AML patients and 53 healthy controls was evaluated by qRT-PCR. Then, the obtained results were interpreted using statistical analysis. Results: In this study, 54 patients with AML were studied. 35% of the patients were female and 65% were male. The mean age of patients was 42.05 years. Hematological findings showed that the number of white blood cells and platelets as well as hemoglobin in patients was significantly different from healthy individuals (P <0.05). Classification of patients based on FAB subgroups showed that most patients (50%) belong to M4 subgroup. Gene expression studies showed that PLOD1 and PLOD3 gene expression was significantly increased in AML patients compared to healthy controls (P value = 0.0002 and P value = <0.0001, respectively). But there was no significant difference in PLOD2 gene expression in AML patients compared to normal control group (P value = 0.3). Summary/Conclusion: Expression of PLOD1 and PLOD3 genes in patients with acute myeloid leukemia has significantly increased compared to the healthy control group and may be used as a prognostic factor in AML patients. There was no significant difference in PLOD2 gene expression in AML patients compared to the normal control group. However, due to the heterogeneity of AML, further studies are needed in different AML subgroups based on FAB and cytogenetic classification.
PB1790: ABCB1 AS A POTENTIAL BENEFICIAL TARGET OF MIDOSTAURIN IN ACUTE MYELOID LEUKEMIA
Authors: S. Sucha, A. Sorf, M. Svoren, D. Vagiannis, F. Ahmed, B. Visek, M. Ceckova
Journal: HemaSphere (2022)

Background: In AML, therapeutic outcome of anthracycline-based induction therapy often can be compromised by a resistant phenotype associated with overexpression of ABCB1 transporters. Novel anti-AML agent, midostaurin, was designed to aim at multiple targets including FLT3 mutation. Besides, it was also identified as ABCB1 inhibitor. Aims: To evaluate ABCB1 efflux activity and expression in primary AML samples in relation to multiple clinical parameters and investigate ABCB1 regulation by microRNA. Methods: ABCB1 gene expression was absolutely quantified in 28 primary AML samples collected prior to any treatment. Efflux activity was examined using combination of mitoxantrone (ABCB1 substrate) and midostaurin (ABCB1/FLT3 inhibitor). Results were compared in molecular classes defined by CD34 marker, FLT3-ITD and NPM1 mutations, ELN risk classification and (un)achieved complete remission (CR). Enhancement of daunorubicin proapoptotic effect mediated by midostaurin was determined in HL-60 wt and HL-60 overexpressing ABCB1. ABCB1 regulation by microRNAs (miR-9, miR-27a, miR-331) was evaluated by ddPCR and correlated with ABCB1 efflux activity. Results: High ABCB1 expression was associated with unachieved CR, adverse ELN risk and CD34 positivity. ABCB1 efflux activity was observed in a functional study when mitoxantrone accumulation increased as a direct consequence of midostaurin in CD34+ AML and patients with unachieved CR. ABCB1 efflux activity and expression were found to be linked to miR-9 downregulation Summary/Conclusion: We propose therapeutic value of midostaurin for drug-resistant patients beyond the FLT3 inhibition based on ABCB1 expression and CD34 positivity. We also propose miR-9 as a predictive ABCB1-related biomarker that could be helpful in identifying ABCB1-resistant AML phenotype.
Outcomes and patterns of treatment in chronic myeloid leukemia, a global perspective based on a real-world data global network
Authors: A. Sanz, R. Ayala, G. Hernández, N. Lopez, D. Gil-Alos, R. Gil, R. Colmenares, G. Carreño-Tarragona, J. Sánchez-Pina, R. A. Alonso, N. García-Barrio, D. Pérez-Rey, L. Meloni, M. Calbacho, J. Cruz-Rojo, M. Pedrera-Jiménez, P. Serrano-Balazote, J. de la Cruz, J. Martínez-López
Journal: Blood Cancer Journal (2022)
PB2080: EFFICACY AND SAFETY OF BENDAMUSTINE-BASED REGIMENS AS FIRST-LINE TREATMENT FOR INDOLENT B-CELL NON-HODGKIN LYMPHOMA: A PROSPECTIVE, MULTICENTER, REAL-WORLD STUDY IN CHINA
Authors: S. Li, S.-J. Wen, J. Ma
Journal: HemaSphere (2022)

Background: Indolent non-Hodgkin lymphoma is typically responsive to initial immune-chemotherapy, but it is also prone to persistent recurrence. Bendamustine, an alkylating agent with properties of a purine analog, has been approved for first-line treatment of indolent non-Hodgkin lymphoma in Japan. Although China has approved the second-line treatment of bendamustine for indolent B-cell non-Hodgkin lymphoma in 2019, evidence of bendamustine as first-line treatment for this patient population in China is still scanty currently. Aims: To evaluate the efficacy and safety of bendamustine-based regimens as first-line treatment for Chinese patients with indolent B-cell non-Hodgkin lymphoma in real-world setting. Methods: Treatment-naïve patients with indolent B-cell non-Hodgkin lymphoma were enrolled in this prospective, multicenter, single-arm, real-world study (ChiCTR2000039605). Eligible patients will be given 4-6 cycles (4 weeks/cycle) of bendamustine-based regimens including bendamustine monotherapy (90 mg/m2 on Day 1-2), bendamustine (90 mg/m2 on Day 1-2) plus rituximab (375 mg/m2 on Day 1), bendamustine (70 mg/m2 on Day 1-2) plus rituximab and cytarabine (500 mg/m2 on Day 2-4), or bendamustine (90 mg/m2 on Day 1-2) plus rituximab and bortezomib (1.6 mg/m2 on Day 1, 8 and 15). Tumor response was assessed by independent central review according to Lugano 2014 response criteria. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR) and safety. Results: Between December 2019 and February 2022, 29 patients were enrolled in this study. The median age of the 29 patients was 63.0 years (range, 35.0-83.0 years). Majority of patients were female (17/29, 58.6%), had stage II-IV disease (23/29, 79.3%), had an International Prognostic Index (IPI) score of 0-2 (20/29, 69.0%), and had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (21/29, 72.4%). Sixteen patients (55.2%) completed 6 cycles of treatment, and 22 patients (75.9%) completed 4-6 cycles of treatment. Of the 29 patients, 19 (65.5%) achieved a complete response, 5 (17.2%) achieved a partial response, 1 (3.5%) had a stable disease, and 4 unknown (13.8%). The ORR and DCR were 82.8% (95% CI, 64.2-94.2%) and 86.2% (95% CI, 68.3-96.1%), respectively. Hematological and non-hematological adverse events were reported in 75.9% and 17.2% of patients, respectively. Summary/Conclusion: Bendamustine-based regimens as first-line treatment were effective and well-tolerated in patients with indolent B-cell non-Hodgkin lymphoma, suggesting that this first-line regimen might offer a potential therapeutic option for this patient population in China.
P1393: HIGHER DOSE OF CD34+ CELLS PROMOTES EARLY RECONSTITUTION OF NATURAL KILLER CELLS AND IS ASSOCIATED WITH BETTER OUTCOMES AFTER UNMANIPULATED HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MYELOID MALIGNAN
Authors: F. Zhao, E. Jiang
Journal: HemaSphere (2022)

Background: Natural killer (NK) cells are potent effectors for eliminating myeloid leukemia and this effect is particularly robust after T-cell-deplete allogenic hematopoietic stem cell transplantation (allo-HSCT). The significance of NK cells after unmanipulated transplantation is less clear and factors affecting early NK reconstitution remain elusive. Aims: To evaluate early NK reconstitution and its effects on HSCT outcomes and related factors. Methods: This study retrospectively analyzed a cohort of 180 allo-HSCT recipients who received unmanipulated grafts between June 2012 and May 2020. All patients have acute myeloid leukemia or myelodysplastic syndrome, and most of the patients and donors (99%) are serologically positive for cytomegalovirus (CMV). NK counts in the peripheral blood at 30 days after allo-HSCT (NK30) are strongly associated with all-cause mortality and a cut-off value at 90 cell/µl is determined for further prognostic analysis. Results: Higher NK30 is associated with reduced disease relapse (HR 0.56, P = 0.02), lower CMV reactivation (HR 0.41, P = 0.001) and better survival (HR 0.43, P = 0.01). Further analysis finds that NK30 is associated with the dose of CD34+ cells (r = 0.739, P < 0.001) and not the numbers of mature NK cells in the graft. In flow cytometric analysis of cryopreserved day +30 bone marrow samples, patients in continuous complete remission (N = 6) demonstrate higher frequencies of CD34+CD7+ progenitor cells and CD56bright NK cells as compared to patients with disease relapse within 1 year (N = 6). No suppressive effect of T cells on NK recovery is found since the majority of patients (131/180, 72.8%) received rabbit anti-thymocyte immunoglobulin (ATG) in the conditioning regimen. Summary/Conclusion: Higher dose of CD34+ cells promotes early recovery of NK cells after allo-HSCT with unmanipulated graft and NK30 represents a valuable prognostic marker of better outcomes. Our data thus provide new information for the therapeutic manipulation of NK cells for the promotion of transplant outcome.
PB2119: LONG-TERM SURVIVAL PROJECTIONS OF LONCASTUXIMAB TESIRINE-TREATED PATIENTS IN RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
Authors: M. Hamadani, C. N. Graham, L. Liao, K. H. Zhang, H. Strat, D. Ungar, W. Ai, L. Chen, C. Carlo-Stella
Journal: HemaSphere (2022)

Background: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA approved CD19-directed antibody-drug conjugate for R/R DLBCL. From the LOTIS-2 trial primary data cut (April 6, 2020), overall response rate was 48.3% and median overall survival (OS) was 9.9 months. The OS Kaplan-Meier (KM) plot displayed a survival plateau suggesting the presence of long-term survivors (LTS). Aims: Survival analyses were conducted on a more mature data cut (March 1, 2021; median follow-up = 1.7 years, follow-up completeness at median = 81%) to estimate the percentage of LTS and expected lifetime survival (mean OS) for Lonca-treated patients. Methods: Consistent with studies of other R/R DLBCL treatments, identified through a literature review, parametric and mixture cure models were fit utilizing multiple distributions. Flexible cubic spline (hazard scale 1-3 knots) and non-mixture cure analyses were also conducted. Age- and gender-matched United States life table hazards were used in projections for LTS and to ensure modeled hazards were not less than the general population. Best-fit models were determined through fit statistics, KM and fitted curve overlays, and clinical plausibility. The best-fit model from each method was a candidate for overall best fit. A hybrid model following the best-fit parametric/spline model to a defined time point and switching to general population mortality was also constructed. Results: Mixture and non-mixture cure models fit best (individual best fits gamma and Weibull, respectively). Parametric and spline models (individual best fits log-normal and 2 knot models, respectively) did not fit the observed data well nor fit the clinical expectation of long-term survival. Due to better fit, spline models were used in the hybrid model. LTS from the mixture cure and non-mixture cure models were 24-26%. Mixture cure, non-mixture cure, and hybrid model with a 2-year switch point were consistent in survival predictions (6.11 to 6.23 years). In a sensitivity analysis with 3-year switch point in the hybrid model, the estimated survival was shorter (4.96 years) due to the switch point being below the observed survival plateau. Table 1 presents full survival results and fit statistics. Image:Summary/Conclusion: The observed survival plateau suggests Lonca-treated patients may include LTS. Mixture cure, non-mixture cure, and hybrid models fit the trial data well and align on survival projections (6.11-6.23 years). Additional survival follow-up may assist in refining the switch point of the hybrid model and confirm presence of LTS.
PB2218: ASSESSMENT OF CYSTATIN C IN PEDIATRIC SICKLE CELL DISEASE AND B-THALASSEMIA AS A MARKER OF SUBCLINICAL CARDIOVASCULAR DYSFUNCTION: A CASE-CONTROL STUDY
Authors: M. Beshir, D. Hanna, N. Khalifa, E. Baz, A. Elhewala
Journal: HemaSphere (2022)

Background: Cardiovascular complications represent the main determinant of survival in patients with hemoglobinopathies. Serum cystatin C is a well-known marker of nephropathy in sickle cell disease (SCD) and b-thalassemia patients that has recently emerged as a strong predictor of cardiovascular dysfunction in patients with and without kidney disease. Aims: We performed a case control study to determine the role of cystatin C as a predictor of subclinical cardiovascular dysfunction in SCD and b-thalassemia patients. Methods: We enrolled 40 SCD patients with a mean age of 12.4 years, 40 b-thalassemia patients with a mean age of 11.4 years and 40 age and sex-matched controls. We assessed hematological profile, serum ferritin, urinary albumin–creatinine ratio (UACR), serum cystatin C, echocardiography and carotid intima media thickness (CIMT). Results: UACR, cystatin C and CIMT were higher in SCD and b-thalassemia patients compared to controls (p < .001). Significantly higher cystatin C levels were observed in SCD and b-thalassemia patients with nephropathy or left ventricular systolic dysfunction (shortening fraction <30%, or ejection fraction <55%; p < .001). Moreover, SCD patients with pulmonary hypertension had significantly higher cystatin C levels. Cystatin C levels were positively correlated with CIMT in SCD (p = .02) and b-thalassemia patients (p < .001) while negatively correlated with ejection fraction and shortening fraction (p < .001). The cutoff values of cystatin C ≥ 16.03 and ≥ 13.2 (ng/mL) could detect subclinical cardiac dysfunction risk among SCD and b-thalassemia patients respectively. Summary/Conclusion: Cystatin C appears to be a promising marker for subclinical cardiovascular dysfunction in SCD and b-thalassemia patients.
P866: CORRELATIVE ANALYSIS TO DEFINE PATIENT PROFILES ASSOCIATED WITH MANUFACTURING AND CLINICAL ENDPOINTS IN RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS TREATED WITH IDECABTAGENE VICLEUCEL (BB2121)
Authors: J. Rytlewski, J. Fuller, D. R. Mertz, C. Freeman, S. Manier, N. Shah, T. B. Campbell
Journal: HemaSphere (2022)

Background: The anti-B-cell maturation antigen (BCMA) autologous chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel; bb2121) has achieved deep and durable responses in relapsed/refractory multiple myeloma (RRMM) patients (Munshi, N Engl J Med 2021). Prior studies have described the correlation between patient characteristics and clinical outcomes from CD19 CAR T cell therapy (Finney, J Clin Invest 2019; Fraietta, Nat Med 2018). Aims: We sought to define patient profiles correlated with manufacturing and clinical endpoints in RRMM patients treated with ide-cel in clinical trials using unsupervised clustering and multivariate machine learning across multiple key variable domains. Methods: Clinical and manufacturing data were harmonized across 164 RRMM patients treated with ide-cel in KarMMa (NCT03361748) and KarMMa-2 cohort 1 (NCT03601078). Based on individual multivariate importance, 10 selected peripheral blood mononuclear cell (PBMC), drug product (DP), and in-process cell growth variables were used to define patient clusters. Random forest classifiers were generated to identify patient characteristics associated with manufacturing and clinical endpoints. Wilcoxon rank sum and Kruskal-Wallis tests were used to compare 2 and 3+ categorical groups; Cox proportional hazards were used to compare groups with time-to-event data. Results: Using an unsupervised method, 4 patient clusters were identified that represented 10%, 57%, 15%, and 18%, respectively, of the total 164 patients. Cluster 4 was the most favorable and was characterized by a higher frequency of T cells in PBMCs; increased T-cell size during manufacturing; higher DP T-cell transduction, potency, and vector copy number; and ultimately a > 3-fold higher CAR T cell yield compared with the least favorable cluster 1. Cluster 2 contained most patients and was associated with intermediate manufacturing endpoints. Patients in cluster 4 had a higher complete response rate, longer progression-free survival, and were defined by lower tumor burden, higher absolute lymphocyte count (ALC), and longer washout period after alkylator treatment, among others (Table). Image:Summary/Conclusion: The current study identified patient profiles in RRMM using accessible laboratory or medical history data that correlated with longitudinal outcomes. These findings may inform patients likely to achieve improved outcomes with CAR T cell therapy.